Cisplatins have been used widely in clinical medicine as an antitumor drug since its antitumor effect was discovered for cis-dichlorodiaminoplatin. Rosenberg et al. Nature, 1965, 205: 698; Nature, 1972, 222: 385. Although cisplatins exhibit therapeutic effects in cancers such as genitourinary cancer, nasopharyngeal cancer, cephalocircular cancer and lung cancer, these drugs also lead to severe side effects. The undesirable effects, such as nephrotoxicity, neurotoxicity, ototoxicity, nausea, and vomiting, put considerable constraints to dosage and long term use of cisplatins.
Carboplatin, one of the second-generation antitumor drugs of platin analogues, has received worldwide approval and use due to its lower toxicity in comparison to cisplatin. Unfortunately, carboplatin still results in a number of side effects, such as myelosuppression. In addition, carboplatin may be used only for a limited spectrum of cancers. Therefore, the search continues for orally active carboplatin analog compounds that are less toxic, cause less drug-resistance and provide more versatility.
Pharmaceutical co-crystallization has attracted great amount of academic, industrial and therapeutic interests by co-crystallization of two or more pure compounds with crystal engineering to create a new functional material. Specifically, pharmaceutical co-crystals are defined as “co-crystals in which the target molecule or ion is an active pharmaceutical ingredient, API, and it bonds to the co-crystal former(s) through hydrogen bonds.” Almarsson M. and Zaworotko J., Chem. Commun., 2004: 1889. Pharmaceutical co-crystals are nonionic supramolecular complexes and can be used to improve physiochemical property issues such as solubility, stability and bioavailability in pharmaceutical development without changing the chemical composition of the API.
Consequently, it is desirable to improve the physiochemical and therapeutic properties of cisplatin, carboplatin and other platin with co-crystallization technology. In some cases, there is no need to change the basic structure of the platin API, while properties such as solubility, stability, permeability and bioavailability would be improved. For example, it would be possible to significantly enhance the bioavailabiltiy of a platin API with co-crystallization, so that the co-crystal can be therapeutically effective in certain environment of use and maintain the level for a prolonged period of time.
Through the screening of the co-crystal formers suitable for carboplatin, 1,2-cis-cyclobutane dicarboxylate was found as an appropriate co-crystal former in this invention, which effectively meet the envisioned objectives, such as increased solubility, stability and bioavailability and more versatility in pharmaceutical uses.